Nicotinic acetylcholine receptors (nAChRs) belong to the Cys-loop subfamily of pentameric ligand-gated ion channels and can be classified into muscle-type and neuronal subtypes. The neuronal nAChRs comprise twelve subunits (α2-α10 and β2-β4) with different arrangements, while the muscle-type is consisted of four subunits in a single arrangement of α1γα1β1δ (c is replaced by e in the adult). (Lukas, R. J. et al, Pharmacol. Rev. 1999, 51, 397) Two major neuronal receptors a4b2 and a7 have been identified in the central nervous system. (Flores, C. et al., Mol. Pharmacol. 1992, 41, 31; Lindstrom J. et al, Prog. Brain Res. 1996, 109, 125) The neuronal α7 nAChR has been proposed as a potential therapeutic target for a broad range of neurodegenerative and psychiatric diseases, including Alzheimer's disease, schizophrenia, anxiety, and epilepsy. A variety of selective partial and full agonists have been developed for the α7 nAChR as potential therapeutics. (Jensen A. et al., Prog., Brain Res. 1996) Several α7 nAChR selective agonists (e.g., TC-5619 and MEM-3454) have advanced to clinical trials for Alzheimer's disease and schizophrenia. (Arneric, S. P. et al, Biochem. Pharmacol. 2007, 74, 1092; Mazurov A. et al, Curr. Med. Chem. 2006, 13, 1567; Olincy A., Arch. Gen. Psychiatry 2006, 63, 630) Although extensive efforts have been taken to identify selective α7 nAChR agonists, the development of α7 selective antagonists is relatively limited. Some studies have reported that certain naturally derived compounds may be incorporated as α7 selective antagonists. For example, the krait Bungarus multicinctus derived peptide toxin α-bungarotoxin (α-BTX) and the seeds of Delphinum isolated nonpetide toxin methyllycaconitine (MLA) are two frequently used α7 selective antagonists. (Chang, C. C, et al. J. Biomed. Sci. 1999, 6, 368; Davies, A. R., et al. Neuropharmacology 1999, 38, 679)
Unfortunately, α-BTX is a potent antagonist for muscle-type nAChRs as well, and both compounds also inhibit nAChR subtypes α9 and α9α10. (Jensen, A. A., et. al. J. Med. Chem. 2005, 48, 4705) Nevertheless, subtype-selective antagonists may possess intrinsic value as tools to define the roles played by α7 nAChRs in the physiological and pathophysiological processes.
Indeed, and along these same lines, nicotinic acetylcholine receptors have been implicated as possible drug targets in a myriad of various disease states and for use as a possible measure for counter-terrorism purposes.
For example, with regards to various disease states, nAChRs have for some time now been studied in an attempt to find a possible nexus between targeting of the receptor and treatment of small cell lung carcinoma (SCLC). (Sciamanna, J. Neurochem. 69, 2302-2311 1997). While SCLC is a neuroendocrine neoplasm that accounts for a minority of newly diagnosed lung cancers, roughly a quarter, it is quite deadly and patients generally die within a mere year of being diagnosed. Thus, there is a pertinent need for the development of treatments, or means of prophylaxis, that can be administered to a patient in order to mitigate, or achieve complete ablation of, the SCLC disease state.
Despite the attendant need, few, if any, specific treatments are available for SCLC. However, the most current data available in the field indicates that two types of nAChRs can regulate NA and CA influx. Such regulation of calcium and sodium influx has biological and therapeutic ramifications in the treatment of neuroendocrine neoplasms. Thus, in light of the paucity of compounds available that can effectively and specifically target such channels, there still remains a glaring need for rationally based compounds that have the ability to target such receptors.
In addition to developing a more efficacious means for treating SCLC, there is also an attendant need for compounds that may be used to treat the more widespread dilemma of non-small cell lung cancer (NSCLC). In this regard it has been observed that mesothelioma and non-small cell lung cancer express functional nAChR. (Paleari, et al. Int. J. Cancer. 125, 199-211 2009) Thus, there has been speculation that nicotine may play some heretofore-unknown role in contributing to lung cancer pathogenesis via activation of such cellular proliferation pathways as Akt signaling or by inhibiting other natural cellular apoptotic machinery. (Id) However, some studies have indicated that nicotine acts on nAChRs, expressed in NSCLC tumor cells, by activating a proliferative response in such cells. (Id)
Next, despite their distinct disease pathology, it has been discovered that disease states such as cancer and AIDS have a common link via nAChRs. In addition to the need to develop treatments for both small and non-small cell lung cancer, however, there is also a need for compounds or treatment mechanisms that have the ability to effectively combat HIV and AIDS, disease states that also pose a very serious threat to public health worldwide. In fact more than 40 million people are infected worldwide with HIV-1 and an estimated 14,000 new infections occur every day. Since the first cases of AIDS were identified in 1981 the deaths of over 25 million people have been attributed to HIV/AIDS.
As mentioned, alpha-7 nAChRs has been found in lung cancer cells where activation by either natural molecules or compounds in tobacco smoke are shown to promote cancer growth. It has been found that those same alpha-7 nAChRs are upregulated in immune cells in AIDS. This suggests that over activation of alpha-7 receptors in macrophages by the AIDS virus protein, may cause premature cell death. Thus, and at the very least, antagonists to nAChRs are needed to continue to exploit the relationship between cancer, AIDS and nAChR activity, and thus provide treatments for these disease states.
Additionally, nicotinic acetylcholine receptors have been also been implicated to play a role in neurodegenerative diseases and cognitive disease or disoarders. For example, nicotinic acetylcholine receptors have been implicated in disease such as Alzheimer's disease. Buckingham et al, Pharmacological Reviews March 2009 vol. 61 no, 1 39-61. Moreover, α7 nAChR have specifically been identified as playing a some type of role in the etiology and/or pathology of Alzheimer's disease. Jones I W, et al, J Mol Neurosci. 2006; 30 (1-2):83-4.
Nicotinic acetylcholine receptors have been also been suggested to play a role in certain neurodegenerative and cognitive disorders. The alpha7 nicotinic acetylcholine receptor (nAChR) has been thought of as a target for treatment of cognitive dysfunction associated with Alzheimer's disease and schizophrenia. J Pharmacol Exp Ther. 2009 May; 329(2):459-68. Epub 2009 Feb. 17.
However, despite these suggested links to a number of disparate diseases and disorders, there are attendant issues with nicotinic acetylcholine receptors. For example nicotinic acetylcholine receptors represent a complex and diverse set of receptor subtypes. Additionally, prolonged use may lead to desensitization of the receptor. Papke, et al., Journal of Pharmacology and Experimental Therapeutics, May 2009 vol. 329 no. 2 791-807.
These latter factors have made it difficult to work with nicotinic acetylcholine receptors and to develop compounds that are efficacious both in the short and long term.